Thioredoxin Reductase Regulates Angiogenesis by Increasing Endothelial Cell-Derived Vascular Endothelial Growth Factor

Streicher, Katie; Sylte, Matthew J.; Johnson, Sally; Sordillo, Lorraine M.

doi:10.1207/s15327914nc5002_13

Cited by 45 publications

(36 citation statements)

References 54 publications

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“…The thioredoxin (TXN) redox cycle is also involved in antioxidant defense. The cycle contains a family of redox-active proteins responsible for mediating numerous cytoplasmic functions and implicated in control of cell growth (19,21,22 Table 1). The best measure of the extent to which a one SNP tags another SNP is the pairwise correlation coefficient (r p 2 ) because the loss in power incurred by using a marker SNP in place of a true causal SNP is directly related to this measure.…”

Section: Methodsmentioning

confidence: 99%

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Tagging Single-Nucleotide Polymorphisms in Antioxidant Defense Enzymes and Susceptibility to Breast Cancer

et al. 2006

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It is generally believed that the initiation of breast cancer is a consequence of cumulative genetic damage leading to genetic alterations and provoking uncontrolled cellular proliferation and/or aberrant programmed cell death, or apoptosis. Reactive oxygen species have been related to the etiology of cancer as they are known to be mitogenic and therefore capable of tumor promotion. The aim of this study was to assess the role of common variation in 10 polymorphic genes coding for antioxidant defense enzymes in modulating individual susceptibility to breast cancer using a case-control study (N cases = 4,474 and N controls = 4,580). Both cases and controls were from the East Anglian region of the United Kingdom. We have identified a set of 54 single nucleotide polymorphisms (SNPs) that efficiently tag all the known SNPs in the 10 genes and are also expected to tag any unknown SNPs in each gene. We found no evidence for association of common variants in SOD1, SOD2, GPX1, GPX4, GSR, TXNRD1, and TXN2. There was borderline evidence for association of variants in CAT g27168a {P [2 degrees of freedom (df )] = 0.05}, TXN t2715c [P (2 df ) = 0.007], and TXNRD2 A66S and TXNRD2 g23524a (P trend = 0.074 and 0.046, respectively). For TXNRD2 A66S [AS versus AA: odds ratio (OR), 1.05; 95% confidence intervals (95% CI), 0.96-1.15; SS versus AA: OR, 1.12; 95% CI, 0.98-1.29], there are bioinformatics data to suggest that it is functional but confirmation in independent data sets is required before they can be regarded as definitive breast cancer susceptibility alleles. Even if confirmed, these four alleles would account for just 0.32% of the excess familial risk of breast cancer. (Cancer Res 2006; 66(2): 1225-33)

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Section: Methodsmentioning

confidence: 99%

“…TXN is also a key enzyme for DNA synthesis by directly serving as an electron donor to ribonucleotide reductase (20). In addition, the level of TXNRDs in tumor cells is often 10-fold or even greater than in normal tissues and tumor proliferation seems to be crucially dependent on an active thioredoxin system (21,22).…”

Section: Introductionmentioning

confidence: 99%

Tagging Single-Nucleotide Polymorphisms in Antioxidant Defense Enzymes and Susceptibility to Breast Cancer

et al. 2006

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“…Effect of SFN on TrxR1 expression. Inhibition of thioredoxin reductase (TrxR1) has been shown to regulate angiogenesis by increasing endothelial cell-derived VEGF (39). SFN increased TrxR1 expression in both HuVECs and PVC dose-and time-dependently, i.e.…”

Section: Effect Of Sfn On Vegf and Vegfr2 Expressionmentioning

confidence: 99%

Differential effects of sulforaphane in regulation of angiogenesis in a co-culture model of endothelial cells and pericytes

et al. 2017

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Abstract. Aberrant neovascularization supports nutrients and the oxygen microenvironment in tumour growth, invasion and metastasis. Recapitulation of functional microvascular structures in vitro could provide a platform for the study of vascular conditions. Sulforaphane (SFN), an isothiocyanate, has been reported to possess chemopreventive properties. In the present study, the effects of SFN on cell proliferation and tubular formation have been investigated using endothelial cells (ECs) and pericytes in coculture. SFN showed a dosedependent inhibition on the growth of ECs and pericytes with IC 50 values 46.7 and 32.4 µM, respectively. SFN (5-20 µM) inhibited tube formation in a 3D coculture although a lower dose (1.25 µM) promoted 30% more endothelial tube formation than control. Moreover, SFN affected intercellular communication between ECs and pericytes via inhibition of angiogenic factor such as vascular endothelial growth factor (VEGF) expression in pericytes. However, the expression of its receptor (VEGFR-2) was found significantly increased in ECs. These effects were associated with downregulation of prolyl hydroxylase domain-containing protein 1 and 2 (PHD1/2) and activation of hypoxia-inducible factor-1 (HIF) pathway by SFN. Furthermore, thioredoxin reductase-1 was also upregulated by SFN treatment, suggesting that antioxidant and redox regulation are involved in angiogenesis. Taken together, the results of the present study suggest that SFN differentially regulates endothelial cells and pericytes disrupting their interplay through the VEGF-VEGFR signalling pathway. Anti-angiogenesis property of SFN indicates that it has potential role as an anticancer agent. IntroductionAngiogenesis, the growth of new capillary blood vessels, is a normal and vital process in growth, development and wound healing. However, it is also a fundamental step in the growth of tumours. Nutrients and oxygen, supplied by the blood vessels into the tumours, are essential for the growth and progression of malignant tumours beyond the size of 1-2 mm 3 (1). Newly formed blood vessels can facilitate cells escaping through leakage from primary tumour sites to metastasize, the major cause of mortality for cancer patients. Anti-angiogenesis has been recognized as valuable therapy in treatment of various metastatic cancers since the theory was first proposed by Folkman (2,3). Tumour angiogenesis is believed to be regulated by the interactions between pro-angiogenic and anti-angiogenic factors in the tumour microenvironment (4). Angiogenic response is a dynamic process requiring a series of fine-tuned angiogenic signalling and molecular events. Hypoxia is the common inducer of angiogenesis in the core of large tumours stimulating the release of pro-angiogenic factors to promote endothelial cell proliferation, migration, differentiation and self-assembly into vascular-like structures. Subsequently, perivascular cells are recruited to form mature and stable vessels (5).The interaction between endothelial cells (ECs) and pericytes (PVCs) has g...

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“…A clue is provided by a recent study examining the influence of selenium on VEGF production by cultured endothelial cells. 75 Growing these cells in selenium-deficient medium was associated with increased production of VEGF, increased expression of VEGFR-2, and an increase in the proliferation and migration of these cells. In cells with good selenium status, treatment with an inhibitor of thioredoxin reductase replicated the effects of selenium deficiency on endothelial behavior, whereas inhibition of glutathione peroxidase had no influence in this regard; thus, good thioredoxin activity in endothelial cells appears to restrain autocrine production of VEGF as well as VEGFR-2 expression, likely because it influences the oxidation status of cysteine residues in signaling proteins.…”

Section: Selenium and Thioredoxin Reductasementioning

confidence: 98%

Multifocal Angiostatic Therapy: An Update

McCarty

Block

2005

Integr Cancer Ther

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Multifocal angiostatic therapy (MAT) is a strategy that seeks to impede cancer-induced angiogenesis by addressing multiple targets that regulate the angiogenic capacity of a cancer and/or the angiogenic responsiveness of endothelial cells, using measures that are preferentially, but not exclusively, nutraceutical. A prototype of such a regimen has been proposed previously, composed of green tea polyphenols, fish oil, selenium, and high-dose glycine, complementing a low-fat vegan diet, exercise training, and the copper-sequestering drug tetrathiomolybdate (TM). A review of more recent evidence suggests additional agents that could appropriately be included in this regimen and clarifies to some extent the mechanisms of action of its constituents. Diindolylmethane, a widely available crucifera-derived nutraceutical, has inhibited cancer growth in several mouse xenograft models; this effect may be largely attributable to an angiostatic action, as concentrations as low as 5 to 10 µM inhibit proliferation, migration, and tube-forming capacity of human endothelial cells in vitro, and a parenteral dose of 5 mg/kg markedly impairs matrigel angiogenesis in mice. Silymarin/silbinin, which has slowed the growth of human xenografts in a number of studies, suppresses the proliferation, migration, and tube-forming capacity of endothelial cells and inhibits vascular endothelial growth factor (VEGF) secretion by a range of human cancer cell lines, in concentrations that should be clinically feasible. The angiostatic activity of orally administered green tea now appears likely to reflect inhibition of the kinase activity of VEGFR-2. Glycine's angiostatic activity may be attributable to a hyperpolarizing effect on endothelial cells that decreases the activity of NADPH oxidase, now known to promote tyrosine kinase signaling in endothelial cells. The ability of TM to suppress cancer cell production of a range of angiogenic factors results at least in part from a downregulation of NF-κB activation. Dual-purpose molecular targets, whose inhibition could be expected to decrease the aggressiveness and chemoresistance of cancer cells while simultaneously impeding angiogenesis, include NF-κB, cox-2, c-Src, Stat3, and hsp90; drugs that can address these targets are now in development, and salicylates are notable for the fact that they can simultaneously inhibit NF-κB and cox-2. The potential complementary of the components of MAT should be assessed in nude mouse xenograft models.

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Thioredoxin Reductase Regulates Angiogenesis by Increasing Endothelial Cell-Derived Vascular Endothelial Growth Factor

Cited by 45 publications

References 54 publications

Tagging Single-Nucleotide Polymorphisms in Antioxidant Defense Enzymes and Susceptibility to Breast Cancer

Tagging Single-Nucleotide Polymorphisms in Antioxidant Defense Enzymes and Susceptibility to Breast Cancer

Differential effects of sulforaphane in regulation of angiogenesis in a co-culture model of endothelial cells and pericytes

Multifocal Angiostatic Therapy: An Update

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